Time filter

Source Type

Cappoen D.,Scientific Institute of Public Health Site Ukkel | Vajs J.,University of Ljubljana | Uythethofken C.,Scientific Institute of Public Health Site Ukkel | Virag A.,University of Ljubljana | And 8 more authors.
European Journal of Medicinal Chemistry | Year: 2014

The rapid generation and spread of the drug resistant tuberculosis has led to an ongoing demand for novel compounds for therapeutic use. Identification and study of compounds with the ability to inhibit Mycobacterium tuberculosis is of paramount importance. For this reason, a library of substituted 1,3-diaryltriazenes based on the acting component of the anti-trypanosomal drug, diminazene aceturate was created and evaluated for its potential as anti-tubercular agent. Several compounds were identified with sub-micro molar inhibitory concentrations against M. tuberculosis and other clinically relevant mycobacterial species such as Mycobacterium bovis, Mycobacterium avium and Mycobacterium ulcerans. Although the library of the compounds showed a considerable acute cytotoxicity, a genotoxicity could not be observed. Finally, the triazene 14 was selected with the best biological properties (IC 50 = 3.26 μM, NI50 = 24.22 μM, SI = 7.44). The compound 14 showed the ability to inhibit the growth of intracellular replicating and multi-drug resistant M. tuberculosis. The results suggest the molecule to be an interesting scaffold for further study and optimization. © 2014 Elsevier Masson SAS. All rights reserved.


Mertens B.,Scientific Institute of Public Health Site Elsene | Van Hoeck E.,Scientific Institute of Public Health Site Elsene | Blaude M.-N.,Scientific Institute of Public Health Site Elsene | Simon C.,University of Liège | And 9 more authors.
Food and Chemical Toxicology | Year: 2016

Since the European Commission prohibited the use of bisphenol A in the production of polycarbonate (PC) baby bottles, many other materials have replaced PC for the manufacture of this type of food contact materials. In the present study, the potential migration risks associated with these alternative materials were investigated. First, all substances were evaluated for endocrine disruptive (ED) activity by using different existing lists of (suspected) ED chemicals. Next, the potential non-ED risks were assessed. A distinction was made between migrants listed in Annex I of European Regulation 10/2011 and the unlisted substances (e.g. non-intentionally added substances). For the listed substances, concentrations in the migration solutions were compared to their respective specific migration limits (SML) (when applicable). Migration of all substances was shown to be below their SML. The unlisted substances were evaluated using toxicological information from previous evaluations, or if not available, by applying the Threshold of Toxicological Concern (TTC) approach. In case the estimated exposure to the unlisted substance exceeded the human exposure TTC value, a more indepth risk assessment was performed. Based on the results of both parts of the study, four baby bottles were considered of high concern because of the potential toxicity of migrating compounds. © 2016 Elsevier Ltd


PubMed | Vrije Universiteit Brussel, CODA CERVA, University of Antwerp, Scientific Institute of Public Health Site Elsene and University of Liège
Type: | Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association | Year: 2016

Since the European Commission prohibited the use of bisphenol A in the production of polycarbonate (PC) baby bottles, many other materials have replaced PC for the manufacture of this type of food contact materials. In the present study, the potential migration risks associated with these alternative materials were investigated. First, all substances were evaluated for endocrine disruptive (ED) activity by using different existing lists of (suspected) ED chemicals. Next, the potential non-ED risks were assessed. A distinction was made between migrants listed in Annex I of European Regulation 10/2011 and the unlisted substances (e.g. non-intentionally added substances). For the listed substances, concentrations in the migration solutions were compared to their respective specific migration limits (SML) (when applicable). Migration of all substances was shown to be below their SML. The unlisted substances were evaluated using toxicological information from previous evaluations, or if not available, by applying the Threshold of Toxicological Concern (TTC) approach. In case the estimated exposure to the unlisted substance exceeded the human exposure TTC value, a more indepth risk assessment was performed. Based on the results of both parts of the study, four baby bottles were considered of high concern because of the potential toxicity of migrating compounds.


PubMed | Vrije Universiteit Brussel, CODA CERVA, University of Antwerp, Scientific Institute of Public Health Site Elsene and University of Liège
Type: | Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association | Year: 2016

Due to the worldwide concern that bisphenol A might act as an endocrine disruptor, alternative materials for polycarbonate (PC) have been introduced on the European market. However, PC-replacement products might also release substances of which the toxicological profile--including their genotoxic effects--has not yet been characterized. Because a thorough characterization of the genotoxic profile of all these substances is impossible in the short term, a strategy was developed in order to prioritize those substances for which additional data are urgently needed. The strategy consisted of a decision tree using hazard information related to genotoxicity. The relevant information was obtained from the database of the European Chemicals Agency (ECHA), in silico prediction tools (ToxTree and Derek Nexus(TM)) and the in vitro Vitotox() test for detecting DNA damage. By applying the decision tree, substances could be classified into different groups, each characterized by a different probability to induce genotoxic effects. Although none of the investigated substances could be unequivocally identified as genotoxic, the presence of genotoxic effects could neither be excluded for any of them. Consequently, all substances require more data to investigate the genotoxic potential. However, the type and the urge for these data differs among the substances.


Cappoen D.,Scientific Institute of Public Health WIV ISP Site Ukkel | Forge D.,University of Mons | Vercammen F.,Scientific Institute of Public Health WIV ISP Site Ukkel | Mathys V.,Scientific Institute of Public Health Site Ukkel | And 7 more authors.
European Journal of Medicinal Chemistry | Year: 2013

A series of bisbenzaldehydes and structurally related analogs, conveniently synthesized via microwave-assisted reactions, were evaluated in vitro against drug susceptible and multi-drug resistant Mycobacterium tuberculosis, against virulent Mycobacterium bovis, against Mycobacterium ulcerans and against two Mycobacterium avium subspecies. Among the 33 substances that were tested, compound 12, i.e. 4,4′-[1,12-dodecanediyl(oxy)]bisbenzaldehyde, emerged as the most promising hit. Its activity was further confirmed in an intracellular growth inhibition assay of M. tb in murine J774 A.1 macrophages. None of the compounds showed significant cytotoxicity on human C3A hepatocytes in a neutral red dye uptake assay and no genotoxicity or mutagenicity was observed as demonstrated by a VITOTOX™ test and confirmed with a comet assay. © 2013 Elsevier Masson SAS. All rights reserved.


Claes P.,Ghent University | Cappoen D.,Scientific Institute of Public Health Site Ukkel | Mbala B.M.,Ghent University | Jacobs J.,Ghent University | And 6 more authors.
European Journal of Medicinal Chemistry | Year: 2013

Identification and investigation of novel classes and compounds for the treatment of tuberculosis remains of utmost importance in the fight against the disease. Despite many efforts, the weakly gram positive Mycobacterium tuberculosis keeps demanding its toll in human lives. For this reason a small library of substituted and unsubstituted aza analogues of cleistopholine and sampangine were synthesized in a short and straightforward manner and tested in vitro against M.tb. The compounds showed promising activity against the M.tb H37Rv strain and Minimal Inhibitory Concentrations (MIC) could be observed as low as 0.88 μM. Accompanied by moderate acute toxicity against C3A hepatocytes, the therapeutic index showed an acceptable range. Further tests con firmed the inhibition by up to 74% of intracellular growth of M.tb inside macrophages conferred by1-hydroxybenzo[g]isoquinoline-5,10-diones. Activity of the library against other clinically relevant mycobacterial species such as Mycobacterium bovis, Mycobacterium avium and Mycobacterium ulcerans was confirmed. Furthermore the activity against a multi-drug-resistant MDR LAM-1 M.tb strain was tested and the MIC value situated around 1 μM. The lacking genotoxicity of a group of enamine substituted cleistopholine analogues indicates this group as a hit and encourages their use as a scaffold for further studies. © 2013 Elsevier Masson SAS. All rights reserved.


Claes P.,Ghent University | Cappoen D.,Scientific Institute of Public Health Site Ukkel | Uythethofken C.,Ghent University | Jacobs J.,Ghent University | And 6 more authors.
European Journal of Medicinal Chemistry | Year: 2014

Given the re-emergence of tuberculosis in Europe and beyond, the search for novel bio-active compound classes against this disease is of utmost importance. As a result of a high intrinsic tolerance of the etiological agent, Mycobacterium tuberculosis, towards most antibiotics and xenobiotics, the search for such new compounds is far from trivial. Further exacerbated by the rapid generation and spread of drug resistant M. tuberculosis and fuelled by the HIV/AIDS pandemic, halting the tuberculosis epidemic is of paramount importance. As part of our program to design new 2-aza-anthraquinones with anti-mycobacterial activity, various dialkyltetrahydrobenzo[g]pyrimido[4,5-c] isoquinolinetetraones were designed and synthesised. The compounds were submitted to a biological evaluation in which the activity against M.tb H37Rvlux was observed, as well as the acute toxicity towards J774 A.1 macrophages. From these results, the selectivity index was calculated. Furthermore, the activity of the most promising compounds was further studied against a multi-drug resistant LAM-1 strain and against intracellular replicating M.tb. The study was further extended with a comet assay and a VITOTOX™ assay to investigate the possibility of observable genotoxic effects caused by these compounds. © 2014 Elsevier Masson SAS. All rights reserved.


Cappoen D.,Scientific Institute of Public Health Site Ukkel | Claes P.,Ghent University | Jacobs J.,Ghent University | Anthonissen R.,Scientific Institute of Public Health Site Elsene | And 5 more authors.
Journal of Medicinal Chemistry | Year: 2014

Tuberculosis (TB) continues to be a worldwide health problem with over 1.4 million deaths each year. Despite efforts to develop more effective vaccines, more reliable diagnostics, and chemotherapeutics, tuberculosis remains a threat to global health, fueled by the HIV pandemic and the rapid generation of drug resistance the exploration of novel drugs to serve as a companion drug for existing drugs is of paramount importance. As part of our program to design new 2-aza-anthraquinones with antimycobacterial activity, various tetrahydro- and octahydrobenzo[j]phenanthridinediones were synthesized these compounds showed high in vitro potency against Mycobacterium tuberculosis, the etiological agent of TB and against other clinically relevant mycobacterial species at submicromolar concentrations the susceptibility of a multidrug resistant strain toward these compounds and their ability to target intracellular replicating Mycobacterium tuberculosis was demonstrated. Next to the acute toxicity, the genotoxicity of these compounds was investigated. Often overlooked in studies, genotoxicity could be dismissed for the investigated compounds, making them a promising scaffold in TB drug research. © 2014 American Chemical Society.


Demeyer D.,Superior Health Council | Demeyer D.,Ghent University | Mertens B.,Superior Health Council | Mertens B.,Scientific Institute of Public Health Site Elsene | And 3 more authors.
Critical Reviews in Food Science and Nutrition | Year: 2016

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the world. The vast majority of CRC cases have been linked to environmental causes rather than to heritable genetic changes. Over the last decades, epidemiological evidence linking the consumption of red and, more convincingly, of processed red meat to CRC has accumulated. In parallel, hypotheses on carcinogenic mechanisms underlying an association between CRC and the intake of red and processed red meat have been proposed and investigated in biological studies. The hypotheses that have received most attention until now include (1) the presence of polycyclic aromatic hydrocarbons and heterocyclic aromatic amines, two groups of compounds recognized as carcinogenic, (2) the enhancing effect of (nitrosyl)heme on the formation of carcinogenic N-nitroso compounds and lipid peroxidation. However, none of these hypotheses completely explains the link between red and processed red meat intake and the CRC risk. Consequently, scientists have proposed additional mechanisms or refined their hypotheses. This review first briefly summarizes the development of CRC followed by an in-depth overview and critical discussion of the different potential carcinogenic mechanisms underlying the increased CRC risk associated with the consumption of red and processed red meat. © 2016, Published with license by Taylor and Francis Group.


Cappoen D.,Scientific Institute of Public Health Site Ukkel | Jacobs J.,Ghent University | Nguyen Van T.,Ghent University | Claessens S.,Ghent University | And 7 more authors.
European Journal of Medicinal Chemistry | Year: 2012

In 1991, WHO recognized the resurgence of tuberculosis as a global health problem. Although modern chemotherapy is effective against the causative pathogen Mycobacterium tuberculosis, the current drug regimens have failed to eradicate the disease. The success of the pathogen, partially attributed to drug resistance, necessitates the development of novel anti-tuberculosis drugs. Benzo[j]phenanthridine-7,12-diones, tetracyclic derivatives of the natural product benz[g]isoquinoline-5,10-dione, were conveniently synthesized via palladium-catalyzed intramolecular cyclization of N-methanesulfonyl-3-bromo-2- (arylamino)methyl-1,4-naphthoquinones. Here we report on the bioactivity of eight benzo[j]phenanthridine-7,12-dione derivatives as candidate drug molecules against M. tuberculosis and on their cytotoxicity on C3A human hepatocytes. The strongest antimicrobial activity (as detected by growth inhibition of bacteria, using luminometry and BACTEC 460-TB) and lowest cytotoxicity was found for 3-methylbenzo[j]phenanthridine-7,12-dione 5e, which was also effective in targeting intracellular M. tuberculosis (in murine J774 macrophages) and was not genotoxic for C3A hepatocytes. © 2011 Elsevier Ltd. All rights reserved.

Loading Scientific Institute of Public Health Site Elsene collaborators
Loading Scientific Institute of Public Health Site Elsene collaborators